Bispecific binding molecules that are capable of binding CD137 and tumor antigens, and uses thereof

Inventors

Liu, Liqin • Lam, Chia-Ying Kao • Diedrich, Gundo • Johnson, Leslie S. • Moore, Paul A. • Bonvini, Ezio

Assignees

Macrogenics Inc

Abstract

The present invention is directed to binding molecules that possess one or more epitope-binding sites specific for an epitope of CD137 and one or more epitope-binding sites specific for an epitope of a tumor antigen (“TA”) (e.g., a “CD137×TA Binding Molecule”). In one embodiment, such CD137×TA Binding Molecules will be bispecific molecules, especially bispecific tetravalent diabodies, that are composed of two, three, four or more than four polypeptide chains and possessing two epitope-binding sites each specific for an epitope of CD137 and two epitope-binding sites each specific for an epitope of a TA. Alternatively, such CD137×TA Binding Molecules will be bispecific molecules, especially bispecific trivalent binding molecules composed of three or more polypeptide chains and possessing one or two epitope-binding sites each specific for an epitope of CD137 and one or two epitope-binding sites each specific for an epitope of a TA. The CD137×TA Binding Molecules of the invention are capable of simultaneous binding to CD137, and a TA. The invention is directed to pharmaceutical compositions that contain any such CD137×TA Binding Molecules. The invention is additionally directed to methods for the use of such molecules in the treatment of cancer and other diseases and conditions. The invention also provides novel CD137-binding molecules, and HER2/neu-binding molecules, as well as derivatives thereof and uses thereof.

Core Innovation

The invention relates to CD137×TA Binding Molecules and their use in treating cancer. A therapeutically effective amount of a composition comprising a CD137×TA Binding Molecule is administered to a subject in need thereof, and the cancer is characterized by the expression of the TA. The CD137×TA Binding Molecule comprises a CD137 binding domain capable of specific binding to an epitope of CD137 and a TA binding domain capable of specific binding to an epitope of a tumor antigen (TA).

The CD137 binding domain includes a first Light Chain Variable Domain with CDRL1, CDRL2, and CDRL3, and a first Heavy Chain Variable Domain with CDRH1, CDRH2, and CDRH3. The first Light Chain CDRs and first Heavy Chain CDRs are specified as CDRs from CD137 MAB-3 variable domains and related variants, including CD137 MAB-3 VL and VH variants, with additional specified pairings among CD137 MAB-3, CD137 MAB-4, and CD137 MAB-5 variable domain CDR sets.

The TA binding domain similarly includes a second Light Chain Variable Domain with CDRL1, CDRL2, and CDRL3, and a second Heavy Chain Variable Domain with CDRH1, CDRH2, and CDRH3. The patent text further describes bispecific binding molecules including tetravalent diabodies, trivalent formats, DART® diabody formats, covalent heterodimeric diabody designs, optimized DART-G3 and optimized DART-G4, trivalent CD137×CD137×TA binding molecules TRIDENT-A and TRIDENT-B, and pharmaceutical compositions containing the CD137×TA binding molecules for cancers characterized by expression of the TA.

Claims Coverage

Two independent claim themes are presented: a method of treating cancer by administering a therapeutically effective amount of a CD137×TA Binding Molecule composition, and the definition of the molecule by CD137-binding and TA-binding domains. The claims center on cancer characterized by TA expression and on specified variable-domain CDR sets, with trivalent formats also described in the patent text.

Overall, the claims are anchored on treating cancer characterized by TA expression using a CD137×TA Binding Molecule, with CD137-binding and TA-binding domains defined by specified light-chain and heavy-chain variable-domain CDR sets.

Stated Advantages

Documented Applications